Neurofibromatosis: causes, symptoms, diagnosis, treatment

Neurofibromatosis (Recklinghausen's disease) is a hereditary disease characterized by malformations of the ecto- and mesodermal structures, primarily the skin, nervous and skeletal systems, with an increased risk of developing malignant tumors.

Neurofibromatosis is a relatively common, highly penetrant, autosomal dominantly inherited disease with variable expressivity, belonging to the group of phakomatoses. High frequency (almost half of the cases) of new mutations has been proven. According to the classification of VM Riccardi (I982), seven types of the disease are distinguished. The most common (85% of all cases) is type I (syn.: classical neurofibromatosis, peripheral neurofibromatosis, Recklinghausen's disease), the gene locus of which is 17q 11.2. Genetic independence of type II (central neurofibromatosis, bilateral acoustic neuroma) has also been proven, the gene locus is 22qll-13.1.

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Causes and pathogenesis of neurofibromatosis

Recklinghausen's disease is an autosomal dominant disorder, the gene locus is 17q 11.2. The disease is caused by a spontaneous mutation of the gene. The absence of neurofibromatosis as a result of a gene mutation can contribute to the onset of the tumor process. Most cases are the result of new mutations, mainly of paternal origin.

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Pathomorphology of neurofibromatosis

Neurofibromas are located in the dermis and upper part of the subcutaneous tissue, do not have a capsule, consist of spindle-shaped and rounded cells. Most tumors have many tissue basophils. The stroma makes up a significant part of the tumor. It is represented by loosely arranged collagen fibers, the bundles of which are intertwined, go in different directions, are palely stained with eosin, as well as thin-walled vessels. Tissue basophils and macrophages are located perivascularly. Immunomorphological studies have shown that collagen types I and III predominate in the stroma. The presence of a large amount of collagen type III indicates the immaturity of the tumor. A positive reaction to the S-100 protein, a marker of neurogenic cells, indicates the neurogenic origin of the neoplasm. Sometimes mucoid dystrophy of the stroma is noted in individual areas or in the entire tumor, revealed as metachromasia when stained with toluidine blue. Histological variants of neurofibroma are described: myxoid. containing much mucin in the stroma; plexiform, consisting of numerous irregularly shaped nerve bundles embedded in a matrix containing variable amounts of spindle cells, wavy collagen fibers, mucin, and tissue basophils; containing structures resembling tactile corpuscles; pigmented (or melanocytic); resembling protuberant dermatofibrosarcoma.

Electron microscopic examination revealed that the round cells are similar in structure to neurolemmocytes, the fine structure of spindle-shaped cells corresponds to that of perineural fibroblasts. The cytoplasm of neurolemmocytes contains axons, a continuous basal membrane 50-70 nm wide surrounds the cells. Perineural fibroblasts have an elongated shape, thin bipolar processes, along the cell membrane there are pinocytotic vesicles surrounded by a discontinuous, sometimes multilayered basal membrane. The basal membrane surrounding the cells contains collagen types IV and V and laminin. Both types of cells that make up the tumor are capable of synthesizing procollagen. Some authors note the predominance of certain cellular elements in neurofibromas. Tumors consisting exclusively of neurolemmocytes or only of perineural fibroblast-type cells have been described.

Histological examination of the skin from the area of "café au lait" spots reveals a large amount of melanin in the basal and suprabasal spinous epithelial cells. Pigment granules are located both in melanocytes and in epithelial cells. Giant granules (macromelanosomes) of spherical or ellipsoid shape, located not only in the basal layer but also higher, up to the stratum corneum, are characteristic of neurofibromatosis. Electron microscopic examination of these elements showed that melanocytes differ little in structure from similar normal cells. They contain three types of melanosomes: small melanosomes of normal structure (they predominate); larger granular ones of moderate electron density with a compacted center and macromelanosomes - giant pigment granules. Macromelanosomes are usually located near the nucleus, consist of an electron-dense matrix, electron-dense membrane-covered round bodies 40-50 nm in diameter with less dense granules inside and small granules of medium electron density. According to the number and distribution of these components, three types of macromelanosomes are distinguished, which apparently represent different stages of their development.

In the area of pseudoatrophic spots, a decrease in the number of collagen fibers in the dermis and perivascular clusters of cells were found, which are neurolemmocyte-type cells surrounding numerous myelinated and unmyelinated nerve fibers.

Histological examination of the pigment spots on the palms revealed limited acanthosis with elongation of epidermal outgrowths, increased melanin content in the epidermis without an increase in the number of melanocytes. In the underlying dermis, small clusters of spindle-shaped cells and wavy collagen fibers resembling miniature neurofibromas were found.

Schwannomas (neurolemmomas) are encapsulated tumors composed of elongated spindle-shaped cells (Schwann cells) and a fibrillar eosinophilic extracellular matrix.

The areas of accumulation of parallel rows of cells are called Antoni A zones. Parallel rows of cells separated from each other by acellular space form characteristic Verokey bodies. Areas of edematous mucinous stroma are called Antoni B zones.

Histogenesis of neurofibromatosis

Many issues of histogenesis are controversial, the reasons for the clinical polymorphism of the disease are unclear. The concept of neurocristopathy proposed by RP Bolande (1974) allows us to explain the polymorphism of clinical manifestations by a violation of the development of the neural crest, migration, growth and differentiation of its cells. Cells originating from the neural crest are localized in various organs and systems, and their dysfunction in one organ can lead to simultaneous dysfunction in other tissues.

Immunohistochemical studies have shown that neurofibroma cells are of neurogenic origin. Perineural fibroblasts can differentiate from mesodermal elements or from primitive neuroectodermal mesenchyme. Using tissue culture, it has been shown that perineural fibroblasts proliferate under the influence of fibroblast-stimulating factor, but the absence of its stimulating effect on the fibroblast culture of healthy individuals indicates that tumor fibroblasts differ significantly from normal fibroblasts. H. Nakagawa et al. (1984) believe that macromelanosomes are formed in the process of disintegration of complexes of ordinary melanosomes, merging with each other and with lysosomes, forming autophagosomes. In support of this point of view, data are provided on the presence of acid phosphatase in macromelanosomes, which is characteristic of lysosomes, as well as the detection of macromelanosomes in other cells (epitheliocytes, intraepidermal macrophages).

Histopathology of neurofibromatosis

Neurofibromas are characterized by proliferation of spindle-shaped cells with wavy nuclei, fibrous fibers, thin-walled vessels, remnants of nerve bundles, tissue basophils, and in pigment spots - giant pigment granules (macromelanosomes) and DOPA-positive melanocytes. In the active growth stage of neurofibromas, an increase in the amount of acidic mucopolysaccharides is noted.

Symptoms of Neurofibromatosis

The disease usually begins in childhood. The clinical picture is characterized by the appearance of pigment spots and neurofibromas. The earliest sign is multiple, oval, small pigment spots with a smooth surface of a yellowish-brown color (the color of "coffee with milk"). The spots are located mainly on the trunk, in the armpits and inguinal folds. With age, the size and number of spots increase. The second characteristic symptom is neurofibromas (cutaneous and / or subcutaneous) in the form of painless hernia-like protrusions up to several centimeters in diameter. When palpating tumor-like formations, the finger falls as if into a void (the symptom of "falling into a void" or the phenomenon of "bell button"). They have the color of normal skin, pinkish-bluish or brownish, soft consistency or, rarely, dense. Neurofibromas are located mainly on the trunk, but can be found in any area. Sometimes there is diffuse neurofibromatosis with excessive proliferation of connective tissue, skin and subcutaneous tissue with the formation of giant tumors (giant neurofibromas). Plexiform neurofibromas often appear along the course of nerve trunks (cranial nerves, nerves of the neck and limbs). They most often transform into neurofibrosarcomas (malignant schwannomas). In the area of neurofibromas, there may be disturbances of various types of sensitivity. Subjectively, pain, paresthesia, itching are felt. Currently, to establish a diagnosis, it is necessary to take into account the presence of two or more of the following symptoms:

• six or more café-au-lait spots greater than 5 mm in diameter in prepubertal children and greater than 15 mm in postpubertal children;
• two or more neurofibromas of any type or one plexiform neurofibroma;
• small pigment spots resembling freckles in the armpits and groin folds;
• optic nerve glioma;
• two or more Lith's nodes;
• dysplasia of the wing of the sphenoid bone of the skull or thinning of the cortical layer of tubular bones with or without pseudoarthrosis;
• neurofibromatosis in first-degree relatives.

Multiple tumor-like formations can be observed in the oral cavity, in the area of spinal roots, inside the skull, which is manifested by corresponding symptoms. The disease is often combined with pathologies of the musculoskeletal system, nervous, endocrine and cardiovascular systems.

The main skin symptoms of neurofibromatosis type I are pigment spots and neurofibromas. The earliest symptom is large yellowish-brown pigment spots ("café au lait"), either congenital or appearing soon after birth. Small pigment spots, resembling freckles, are located mainly in the armpits and groin folds. Neurofibromas (cutaneous and/or subcutaneous), usually multiple, usually appear in the second decade of life. They have the color of normal skin, pinkish-bluish or brownish. Above deeply located tumors, a herniated protrusion is characteristic, upon palpation of which the finger falls as if into a void. Plexiform neurofibromas, which are diffuse tumor-like growths along the course of nerve trunks, are usually congenital. They can be located both superficially - along the cranial nerves, nerves of the neck and limbs, and deep in the mediastinum, retroperitoneal space, paraspinal. Superficial plexiform neurofibromas can have the appearance of saccular hanging, massive lobular tumors, often hyperpigmented. In their depths, thickened tortuous nerve trunks are palpated (elephanthiasis neurofibromatosa). The presence of a deep plexiform neurofibroma can be indicated by large, hairy pigmented spots, especially those crossing the midline of the body. Plexiform neurofibromas are most often subject to malignancy with the development of neurofibrosarcoma. Other skin manifestations sometimes observed are bluish-blue and pseudoatrophic spots, melanotic spots on the palms and soles, neurinomas. In children, the appearance of juvenile xanthogranulomas often accompanies the development of myelocytic leukemia.

Pathological changes can be observed in almost all organs and systems, most often in the organs of vision, nervous, skeletal and endocrine systems.

The diagnosis of neurofibromatosis type I requires two or more of the following features (WHO, 1992): six or more café-au-lait spots greater than 5 mm in diameter in prepubertal children and/or 15 mm in postpubertal children; two or more neurofibromas of any type or one plexiform neurofibroma; the presence of small pigmented spots resembling freckles in the axillary and inguinal folds; optic glioma; two or more Lisch nodules; sphenoid wing dysplasia or cortical thinning of tubular bones with or without pseudoarthrosis; the presence of neurofibromatosis type I in first-degree relatives according to the same criteria.

Based on the ratio of the main skin manifestations, we identified 4 clinical forms of neurofibromatosis type I: with the presence of predominantly neurofibromas; large pigment spots; generalized small-spotted; mixed.

The development of neurofibromatosis type II (central) is associated with the absence of the primary product of the gene - schwannoma (merlin), which presumably inhibits tumor growth at the level of cell membranes. Skin manifestations may be minimal: pigment spots occur in approximately 42% of patients, neurofibromas - in 19%. More typical are painful, dense and mobile subcutaneous tumors - neurinomas (schwannomas). Bilateral neurinoma (schwannoma) of the auditory nerve develops in almost all cases and causes hearing loss, usually at the age of 20-30 years. The diagnosis of neurofibromatosis type II can be made in the presence of one of the following criteria: radiologically confirmed bilateral acoustic neurinoma; bilateral acoustic neurinoma in a first-degree relative and the presence of any of the following signs in the proband:

• unilateral acoustic neuroma;
• plexiform neurofibroma or two other tumors: meningiomas, gliomas, neurofibromas, regardless of their location;
• any intracranial or spinal tumor.

Type III, or mixed (central-peripheral), neurofibromatosis is characterized by tumors of the central nervous system that develop at the age of 20-30 and, as a rule, progress rapidly. The presence of neurofibromas in the palms is considered a diagnostic criterion that allows differentiating the disease from type II central neurofibromatosis, however, according to our data, neurofibromas on the palms and soles occur in 24% of patients with neurofibromatosis type 1.

Type IV (variant) neurofibromatosis differs from type II central neurofibromatosis by more numerous cutaneous neurofibromas, a greater risk of developing optic nerve glioma, neurolemmas, and meningiomas.

Neurofibromatosis type V - segmental neurofibromatosis, is characterized by unilateral lesions (neurofibromas and/or pigment spots) of any skin segment or part thereof. The clinical picture may resemble hemihypertrophy.

Type VI neurofibromatosis is characterized by the absence of neurofibromas;
only pigment spots are found.

Neurofibromatosis type VII is a late-onset variant of the disease, characterized by the appearance of neurofibromas after the age of 20.

The intestinal form of neurofibromatosis is characterized by the development of intestinal tumors in adults; symptoms characteristic of classical type I are rarely observed.

Pigmented spots may be part of Leschke syndrome. Neurofibromatosis may be associated with Noonan syndrome, pheochromocytoma, and duodenal carcinoid.

Treatment of neurofibromatosis

Large neurofibromas can be removed surgically.